This application proposes a mentoring period of five years that will allow Dr. Howell to make a transition from his basic pharmacology background to the field of environmental toxicology. Dr. Howell joined the Center for Environmental Health Sciences (CEHS) at Mississippi State University in February of 2009 as a non-tenure track assistant research professor. His postdoctoral research at the University of Tennessee Health Sciences Center was on molecular mechanisms of dyslipidemia in hyperinsulinemic states such as type 2 diabetes (T2D). Our current research within the CEHS is examining the relationship between pesticide exposure and cardiovascular disease risk, including paraoxonase activity, in varied subsets of the human population. However, we are also examining the relationship between exposures to persistent organic pollutants, namely the organochlorine compounds, and the occurrence of T2D in these subsets. Thus, Dr. Howell's background in molecular mechanisms of insulin resistance and dyslipidemia provide a basic mechanisms approach to our current human studies. Although Dr. Howell's doctoral degree is in pharmacology and toxicology, his graduate program and postdoctoral fellowship were pharmacologically based and did not provide him with the working knowledge of toxicological mechanisms and concepts that will allow him to excel in a tenure-track faculty position within the CEHS. It is Dr. Howell's long term goal to obtain a tenure track faculty position within the CEHS here at Mississippi State University where he can be a successful researcher and academic professor. To assist Dr. Howell in making his transition, we have outlined a career development/training plan and a research plan that will allow him to obtain the necessary training in toxicological concepts and methods, enhance his competitiveness as a researcher, and establish his own independent line of research. In order to acquire the needed knowledge of toxicological mechanisms and concepts, Dr. Howell will attend the following graduate level courses in the first two years of this award: (CVM 6513) Environmental Toxicology and (CVM 8543) Mechanisms of Toxic Action. Through completion of these two courses, Dr. Howell will gain a working knowledge of the classes of environmental contaminants and how they affect target organ systems. In addition to didactic lecture, Dr. Howell will become a member of the Society of Toxicology and present his research findings at both regional and national toxicology meetings each year. This will allow Dr. Howell to enhance his presentation skills and network within the toxicology field while he learns where the current emphasis is, what work is being done, and how he can apply this to his research. Over the course of this award, Dr. Howell will also be collaborating with the other investigators within the CEHS, especially his mentor Dr. Jan Chambers, on their current research so that he can gain different experimental perspectives as well as enhance his publication record. To prepare Dr. Howell for the transition to a tenure track position, he will provide guest lectures in our graduate student classes during the last three years of this award where he will be responsible for the formulation of his lectures as well as for testing on his material. In addition to lecturing, Dr. Howell will serve on applicable graduate student committees and help guide their research projects. This will allow him to gain experience in the teaching aspect of academia. To establish his own independent line of research, Dr. Howell will be examining the effect of exposure to organochlorine compounds on the development of obesity and T2D. While there is emerging epidemiological evidence that demonstrates a high association between blood levels of organochlorine compounds, namely oxychlordane and/or DDE, and the occurrence of T2D, there is very little empirical evidence to show causality. Therefore, the current research plan will utilize both in vitro cell culture models of insulin sensitive tissues and an in vivo rodent model to determine if exposure to either oxychlordane or DDE decreases insulin signaling, glucose uptake, and production of adipokines/cytokines that can promote insulin resistance. The current preliminary data indicate that exposure to DDE decreases adipogenesis while increasing the release of leptin and interleukin-6 from adipocytes. Thus, the effect of DDE and oxychlordane exposure on expression and function of adipogenic genes will be explored and the effect of bioaccumulation of both DDE and oxychlordane on adipokine/cytokine expression will be assessed. The effect of exposure to OC compounds on insulin signaling in the skeletal muscle has not been delineated. The current preliminary data indicate that exposure to oxychlordane or DDE decreases insulin stimulated glucose transporter 4 (Glut4) translocation in rat skeletal muscle cells. To more closely examine this observation, the effect of exposure to these two compounds on glucose uptake, Glut4 translocation, and insulin signaling in the skeletal muscle cell and the adipocyte will be explored in vitro. In order to determine if there is a causative relationship between environmentally relevant exposure to DDE and the occurrence of T2D, a high fat diet induced model of T2D (high fat fed C57BL/6J mice) will be employed to determine if this exposure causes or worsens the diabetic state of these animals. Taken together, the currently proposed research will determine whether exposure to DDE facilitates insulin resistance and T2D in the whole animal and will provide mechanistic incite from both target tissues and the whole animal. PUBLIC HEALTH RELEVANCE: The presently proposal seeks to prepare the applicant, George Howell, for an independent research career at Mississippi State University as a tenure-track professor. This proposal outlines a career development plan that will be overseen by his mentor, Jan Chambers, as well as a research plan that will examine the effect of exposure to organochlorine compounds on the development of insulin resistance and T2D. This research will determine if exposure to these compounds is a risk factor for development of T2D and if so will provide mechanisms through which these compounds precipitate this disease.